Cells sense and respond to cues in local their environment, such as signals produced by neighboring cells as well as the chemistry and mechanics of the surrounding matrix. The spatial organization of cells within tissues, or tissue “architecture”, defines the cell-cell contacts and paracrine signaling gradients thought to ultimately drive tissue function. Reconstruction of complex tissues for applications in regenerative medicine requires the ability to build three-dimensional (3D) tissues with multi-cell type environment.
Recent studies have demonstrated that three-dimensional (3D) micro-scale organization of a single cell type dictates cell behavior and function in vitro (Albrecht, D. R., et al. Nat Methods 3, 369-375 (2006); Nelson, C. M., et al. Science 314, 298-300 (2006); and Ungrin, M. D., et al. PLoS One 3, e1565 (2008)). However, the ‘top-down’ dielectrophoresis and molding techniques used in these studies enabled micro-scale organization of only a single cell type in a single engineered tissue layer. Scaling these techniques to enable the organization of multiple cell types across distinct compartments would require separate fabrication of multiple layers followed by tedious manual alignment and lamination. Such assembly prevents patterning of multiple cellular compartments in a single Z plane.
To address this issue, ‘bottom-up’ technologies such as laser and inkjet-based bioprinting have been used to attain multi-cellular 3D spatial organization in a single Z-plane. However, trade-offs between printing time, resolution, and scale-up as well as between cell density and damage have precluded the use of these methods for widely using these methods to study the relationship between tissue architecture and function. A major unmet challenge is to develop robust methods for spatially patterning 3D cell cultures and to then use these methods to understand how complex multi-level tissue structure controls physiologic function in vitro and after implantation.